The RUNX1 gene on human chromosome 21q22.1 belongs to the "runt domain"
gene family of transcription factors (also known as AML/CBFA/PEBP2). In human
three highly conserved runt domain genes have been identified: RUNX1 on chromosome
21q22.1, RUNX2 on chromosome 6p21 and RUNX3 on chromosome 1p36.1. RUNX1 is a
key regulator of hematopoiesis and a frequent target of leukemia associated
chromosomal translocations. RUNX2 on the other hand functions as a key regulator
of osteogenesis. The three RUNX gene-products bind to the same DNA sequence;
therefore, their pleotropic functions must result from a regulated, temporally
specific and tissue-specific expression as well as interactions with other transcriptional
regulators.

Complete DNA sequence of RUNX1 was recently obtained within the framework of
chromosome 21 mapping and sequencing consortium and the structural/functional
features of the gene were established in our lab.

We found that two distinct promoter regions, designated distal (D) and proximal
(P), control the transcription of RUNX1. These promoter regions are separated
by a particularly large intron of 160 Kb. RUNX1 D and P promoters mediate transcription
of mRNAs with discrete 5' UTRs, the D-UTR (0.45 Kb) and P-UTR (1.6 Kb). These
5UTRs function as translational regulators thereby creating an additional
level of control. RUNX1 mRNAs bearing D-UTR are readily translated via cap-dependent
mechanism; wherease translation of mRNAs with the uncommonly long P-UTR is mediated
through usage of the internal ribosome entry site (IRES) of this UTR. The temporal
and spatial expression of RUNX1 promoters during mouse embryogenesis is studied
using promoter-lac-z constructs in transgenic mice. RUNX1 expression also involves
complex patterns of alternative splicing generating a diverse collection of
mRNAs with coding regions varying in size between 188-480 aa. The short proteins
usually lack the so-called transactivation domain (TAD). We showed that one
of the short isoform RUNX1/p26, but not the full length RUNX1/p49, suppressed
in vivo tumor growth and differentiation of ES cells derived teratocarcinomas.
Most TAD containing RUNX proteins terminate with an identical C-terminal VWRPY
motif which serves to recruit the co- repressor Groucho/TLE. We demonstrated
direct interaction between Gro/TLE and RUNX1/p49 and show that this interaction
lead to transcriptional repression of RUNX1 regulated target genes. The protein
isoform RUNX1/p51, which is almost identical to RUNX1/p49 but lacks VWRPY, did
not interact with Gro/TLE. These data highlight the biological significance
of the alternatively spliced RUNX1 isoforms.